Kikuchi–Fujimoto is a

rare lymphohistiocytic disorder

that affects young women of

Asian descent more frequently

than persons of other ethnic groups.

Net-Wing Beetle. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Pathogenesis, Diagnosis, and Management of Kikuchi–Fujimoto Disease Darcie Deaver, PhD, Pedro Horna, MD, Hernani Cualing, MD, and Lubomir Sokol, MD, PhD

Background: Kikuchi–Fujimoto disease (KFD) is a rare lymphohistiocytic disorder with an unknown etiopathogenesis. This disease is misdiagnosed as malignant in up to one-third of cases and is as- sociated with the development of systemic erythematosus (SLE). Methods: The medical literature between the years 1972 and 2014 was searched for KFD, and the data were collected and analyzed regarding the epidemiology, clinical presentations, diagnosis, management, and suggested diagnostic and treatment algorithms. Results: Although KFD has been reported in other ethnic groups and geographical areas, it is more frequently diagnosed in young women of Asian descent. Patients with the disease typically present with rapidly evolving tender cervical , night sweats, , and . Diagnosis is based on histopathological examination. Excisional biopsy is essential for a correct diagnosis. Apoptotic coagulation with karyorrhectic debris and the proliferation of , plasmacytoid dendritic cells, and CD8+ T cells in the absence of are characteristic cytomorphology features. Interface dermatitis at the onset of KFD may be a marker for the subsequent evolution of SLE. The natural course of the disease is typically benign. Short courses of steroids, nonsteroidal anti-inflammatory drugs, or hydroxychloroquine can be administered to patients with more severe symptoms. Conclusions: Although KFD was described more than 40 years ago, the etiology of this disease remains un- solved. Infectious or autoimmune processes were proposed but have not been definitively confirmed. Clinical presentation with systemic B symptoms and adenopathy may lead to an erroneous diagnosis of malignant lymphoma. The introduction of modern methods into , including , , and molecular clonality studies, has decreased the probability of misdiagnosis. Until reliable prognostic markers are available, patients with KFD should have continued long-term follow-up care due to their increased risk of SLE.

From the Departments of Malignant Hematology (DD, LS) and Address correspondence to Darcie Deaver, PhD, Celgene Hematopathology and Laboratory Medicine (PH) at the H. Lee Moffitt Corporation, 1503 Foppiano Loop, Round Rock, TX 78665. Cancer Center & Research Institute, Tampa, Florida, and IHCFLOW E-mail: [email protected] (HC), Lutz, Florida. No significant relationships exist between the authors and the com- Dr Deaver is now affiliated with Celgene Corporation. panies/organizations whose products or services may be referenced Submitted February 18, 2014; accepted July 2, 2014. in this article.

October 2014, Vol. 21, No. 4 Cancer Control 313 Introduction and maculopapular rash. However, no confirmatory Kikuchi–Fujimoto disease (KFD), also known as studies or results from the control samples were avail- Kikuchi disease, is a rare lymphohistiocytic disor- able. Huh et al21 amplified sequences of HHV-8 from der first described in 1972.1,2 KFD generally affects lymph nodes in 6 out of 26 patients with KFD (23%). women of Asian descent between the ages of 20 and They did not detect any viral sequences in the reactive 35 years and has a male:female ratio of 1:2; howev- lymph nodes of the study controls, suggesting that er, new cases of KFD have also been described in HHV-8 may play a role in the of KFD. non-Asian ethnic groups and children in Europe and the United States.3-10 The acute or subacute onset of adenopathy and systemic B symptoms in KFD has his- Zhang et al22 searched for parvovirus B19 in 33 lymph torically led to a misdiagnosis of malignant lymphoma, node samples from patients with KFD and 16 controls although modern hematopathological methods have using several different methods, including PCR, immu- made such misdiagnosis less likely.11-14 Following the nohistochemistry, and in situ hybridization (ISH). A resolution of KFD, concurrent autoimmune disorders significantly higher rate of B19 positivity was seen in have been reported; they may also be more frequently samples from patients with KFD than in controls; B19 diagnosed.15,16 infected cells were mostly composed of lymphocytes and a small number of histiocytes.22 Epidemiology The precise incidence of KFD is unknown; however, Epstein–Barr Virus a large review identified and analyzed 733 patients Hudnall et al23 tested 30 lymph node samples of pa- diagnosed worldwide since 1972.8 Of those cases, 140 tients with KFD and 12 controls for the presence (19%) were pediatric patients, and the male:female of EBV using real-time PCR, EBV-encoded RNA ISH, ratio was 1.4:1.8 (It is worth noting that a higher and EBV latent membrane protein with immunohis- propensity for male sex has only been observed in tochemistry. Cells with apoptotic features positive for children younger than 12 years of age.5) The pre- EBV-encoded RNA were found in the necrotic regions senting symptoms in children are similar to adults, of many KFD cases, suggesting that the disease could although and rash are more frequent in pediatric be due to a hyperimmune reaction against EBV infec- patients.8 Children younger than 18 years of age may tion. Hollingsworth et al24 looked for EBV and HHV-6 also demonstrate bilateral using PCR and ISH in 20 patients with KFD, but the more frequently than adults.9,10 study results did not support a viral role in the patho- The occurrence of KFD in family members has genesis of KFD. However, Yen et al25 reported EBV rarely been described.17 A search for a link between in a child with a cutaneous manifestation of KFD and class 2 alleles KFD, supporting the pathogenic role of EBV infection, in the Japanese population suggested the possibil- and Chiu et al26 detected EBV RNA sequences in all ity of a positive relationship between DPA1*01 and 10 tested samples of KFD but found only a single DPB1*0202 alleles and the disease.18 Because these al- case of EBV-encoded proteins. No evidence of human leles are much more frequent in Japan than in Europe T-lymphotrophic virus or parvovirus B19 was seen in and the United States, this finding may explain the the patient samples of this study.26 higher prevalence of KFD in patients of Asian descent, Overall, the results of studies searching for a viral thus supporting a possible autoimmune pathogenic etiology of KFD have been inconsistent. Laboratory mechanism. methods differed among laboratories, positive results were documented in a small number of samples, and Viral confirmatory studies with control samples were often Epstein–Barr virus (EBV), human herpesvirus (HHV) unavailable. Currently, no definitive evidence suggests types 6, 7, and 8, herpes simplex virus, HIV, human that a known virus plays a key role in the pathogen- T-lymphotrophic virus, and parvovirus B19 are the esis of KFD. most frequently studied viruses in patients with KFD. Autoimmune Mechanism Human Herpesviruses Autoimmune disorders are frequently reported in Cho et al19 studied HHV-6 and HHV-7 in 50 archival patients with KFD, with systemic lupus erythema- samples of KFD and 20 controls using nested poly- tosus (SLE) being the most common disorder linked merase chain reaction (PCR) and found no significant to KFD.27 In many reports, KFD preceded the de- difference in the viral DNA sequences between patients velopment of SLE; however, the diagnosis of KFD and controls. Labrador et al20 identified the DNA of has been reported to simultaneously occur or follow HHV-7 in the affected lymph node of a young patient the diagnosis of SLE.27,28 In one study, patients with with KFD who presented with cervical adenopathy KFD were negative for antinuclear and anti-DNA an-

314 Cancer Control October 2014, Vol. 21, No. 4 tibodies, suggesting that — at least initially — SLE SLE adenopathy is usually mild, generalized, and KFD have distinct pathogenic mechanisms.4 and nontender. The cytomorphology of enlarged A diagnosis of SLE requires at least 4 out of 11 criteria lymph nodes in SLE consists of scattered plasma to be present, and lymphadenitis is not included in cells and immunoblasts, increased vascularity with these criteria.29 Sopeña et al30 found several autoim- Azzopardi phenomenon associated with moderate mune disorders, including SLE, Sjögren syndrome, reactive follicular , or varying degrees of thyroiditis, and leukocytoclastic vasculitis, in 9 (53%) with the presence of hematox- of 20 patients with KFD. ylin bodies (Table 1).4,10,27 These features can help Kim et al31 reviewed patients with KFD in the differentiate involvement with SLE compared with context of SLE and noticed an increasing number KFD.27,34 SLE is also associated with higher antinu- of case reports in the medical literature. Among clear antibody titers and organomegaly, which is a 9 cases of KFD and SLE, 7 patients manifested with rare finding in KFD.35 skin disease. Histological evaluation of skin biopsies was consistent with SLE in 3 of the 7 cases. Com- Molecular Biology monly, patients with a simultaneous onset of KFD Molecular pathways implicated in the pathobi- and SLE have flare-ups of lupus; therefore, some re- ology of KFD are not well understood. Ishimura searchers have suggested that concurrent KFD and et al36 reported on a noninvasive method for di- SLE diagnoses are actually lupus lymphadenitis.31 agnosing KFD using gene expression profiling Other researchers suggest that KFD is a forme fruste on peripheral mononuclear cells. The top 5 up- of SLE.32 Lymphadenitis is not included among the regulated genes included FI44L, CXCL10, GBP1, 11 diagnostic criteria of SLE, so it cannot establish EPSTI1, and IFI27. All 5 genes belong to the a diagnosis of SLE as a sole pathological finding; family of interferon-induced genes. Ohshima however, the simultaneous manifestation of histocytic et al37 investigated and cell-cycle–associ- necrotizing lymphadenitis with skin rash, cytopenias, ated gene expression in lymph nodes from patients arthralgias, and abnormal results on serological tests with KFD and nonspecific lymphadenitis (NSL). should raise suspicion of SLE and a comprehensive The up regulation of nearly all apoptosis-associated work-up should be completed.29 Paradela et al33 re- genes, including caspase, and the down regulation of ported on a patient with KFD and interface dermatitis apoptosis inhibitory genes, such as BCL2, was seen who subsequently developed SLE. They reviewed the in samples with KFD. Cell-cycle–associated genes medical literature and found an additional 27 cases of were up regulated in all patients with KFD, which KFD with simultaneous nodal and cutaneous involve- is in contrast to patients with NSL.37 Ohshima et al38 ment, 9 of whom subsequently developed SLE. Skin studied cytokine pathways in 10 lymph node samples biopsy was consistent with interface dermatitis in all from patients with KFD and 4 controls with NSL us- of the KFD cases that evolved into SLE. The authors ing immunohistochemistry and reverse transcriptase suggested that interface dermatitis could be a valuable PCR. Results of the study suggested that the cytokine marker of evolution of KFD into SLE.33 However, due and chemokine pathways of interferon γ, interleukin to differing opinions about the possibility of concur- 18, MIG, and interferon γ–induced protein 10 play rent diagnoses of KFD and SLE, further research is an important role in the pathogenesis of apoptosis necessary to reach a definitive conclusion. associated with KFD.38

Table 1. — Histopathological Features of Kikuchi–Fujimoto Disease and Systemic Lupus Erythematosus

Cytomorphology Immunohistochemistry

Kikuchi–Fujimoto Disease Distorted nodal architecture with cortical and paracortical CD68+ nodules with proliferation of histiocytes and immunoblasts, CD123+ coagulative necrosis, abundant apoptotic , and + crescentic histiocytic nuclei CD4 CD8 T-cell predominance Myeloperoxidase positive Lysozyme positive T-cell immunoblasts

Systemic Lupus Erythematosus Moderate reactive follicular hyperplasia, scattered plasma CD4+ with predominance over CD8+ T cells cells and immunoblasts, with increased vascularity or varying Lymphoid follicles are mixture of small- degrees of coagulative necrosis with Azzopardi phenomenon and medium-sized lymphocytes and presence of hematoxylin bodies Germinal centers of the B cell are BCL2–

October 2014, Vol. 21, No. 4 Cancer Control 315 Clinical Manifestation Diagnosis KFD frequently manifests as an acute or subacute illness Lymph Node Biopsy with systemic B symptoms and painful posterior cer- Although fine-needle aspiration biopsy (FNAB) is a vical lymphadenopathy (Table 2).1,2,4,10,39 Lymph nodes valuable tool for the diagnosis of some lymphopro- are usually smaller, ranging from 0.5 to 4.0 cm.10,27,40 liferative disorders, particularly in relapse settings, Approximately 1% to 22% of patients develop general- excisional biopsy is the preferred diagnostic tool in ized lymphadenopathy.4,39 Kucukardali et al32 analyzed patients presenting with new adenopathy.27 Tong et 244 patients between 1991 and 2006, most of whom al51 analyzed 44 cases of patients with confirmed were from Taiwan (36%); 15 (6%) were from the United KFD or suggested by FNAB. The false-positive and States. Fever was the most common systemic symptom false-negative rates were 37.5% and 50%, respectively. (presenting in 35% of patients). Lymphadenopathy was The overall accuracy of FNAB was about 56%.51 Das et observed in 100% of patients, erythematous rashes in al52 compared FNAB smears of lymph nodes between 10% of patients, and in 3% of pa- patients with KFD and reactive nodal hyperplasia and tients.32 An association with SLE was seen in 13% of showed overlapping cytological features in both con- patients and viral infections in 10% of patients, although ditions, which suggests the limited diagnostic poten- SLE was more frequent in patients from Asia than Eu- tial of this method. Up to 30% of patients with KFD rope (28% vs 9%).32 The disease was self-limiting in most are initially misdiagnosed, so lymphoma excisional patients (64%), and treatment with was biopsy should be the requested diagnostic method necessary in 16% of patients.32 used for patients with suspected KFD.4,10 Cheng et al41 studied 195 patients who were di- agnosed with KFD between 1989 and 2006 in the Histology and Immunohistochemistry largest retrospective study reported from a single KFD is characterized by a distortion of the normal institution. In this study, 53% of patients presented nodal architecture with cortical and paracortical nod- with tender adenopathy, 38% with fever, and 17% ules with coagulative necrosis and abundant apoptotic with .41 A benign course with a sponta- karyorrhectic debris.1,2,4,10,27 Additional characteristic neous resolution of systemic symptoms and adenop- features include the proliferation of histiocytes and athy was observed in 183 patients (94%); 14 patients immunoblasts with an abundance of CD8+ T cells (15%) developed recurrent disease within 6 months and an absence of neutrophils (Fig 1). Immunohisto- of follow-up; 5 patients (3%) developed autoimmune chemical stains reveal histiocytes expressing CD68, , including SLE (2), Graves disease (2), and myeloperoxidase, and CD4 markers. A predominance mixed connective tissue disease (1); and 1 patient of CD8+ T cells in affected lymph nodes of patients with recurrent KFD died of intracranial hemorrhage with KFD has also been described.53 The expression secondary to thrombocytopenia.41 of the CD123 marker on plasmacytoid dendritic cells also supports a diagnosis of KFD (see Table 1).53 Extranodal Manifestation Kuo et al50 studied 79 cases with KFD and strat- The most commonly affected extranodal organ is the ified KFD into 3 stages according to histopathologi- skin (30%–40%).42,43 Nonspecific variable lesions, in- cluding papules, facial malar erythema, plaques, or Table 2. — Diagnostic Criteria for Kikuchi–Fujimoto Disease nodules, are typically observed.43 Histology of the skin biopsy often resembles that of KFD. Case reports Clinical Localized lymphadenopathy have also indicated an association of KFD with vari- Systemic symptoms ous inflammatory disorders, such as hemophagocytic Fever syndrome, cerebellar ataxia, , conjunctivitis, Fatigue 39,44-49 , and myocarditis. Headache Laboratory Tests Pathological Laboratory studies No specific laboratory test is available for diagnosing Leukopenia KFD. A complete blood count is usually within normal Elevated C-reactive protein range.27 Two large reviews observed leukopenia in Erythrocyte sedimentation rate 19% to 43% and anemia in 23% of people with KFD. Biopsy of the lymph node Other laboratory abnormalities include elevated lev- Aggregates of CD68+ histiocytes with occasional els of erythrocyte sedimentation (40%–79%), lactate crescent-shaped nuclei Foci of ranging from isolated apoptotic dehydrogenase (53%), and alanine aminotransferase cells to large areas of geographical necrosis 32,41 (23%). Circulating atypical lymphocytes have also Proliferation of plasmacytoid dendritic cells been reported in the peripheral blood film of approx- No accumulation of eosinophils or neutrophils imately 25% of patients with KFD.50

316 Cancer Control October 2014, Vol. 21, No. 4 cal features. The proliferative stage is characteristic sis, Bartonella henselae, HIV, and EBV, as well as for the expression of various histiocytes, plasma- connective tissue disorders (eg, SLE) and lymphop- cytoid monocytes, and lymphoid cells containing roliferative disorders (Table 3).4,27 The proliferation karyorrhectic fragments and eosinophilic apoptotic stage of KFD may present with features similar to debris.50 The necrotizing stage can be recognized lymphoma and may lead to misdiagnosis.10,54 The pres- based on the presence of a various degree of coag- ence of large atypical cells and immunoblasts of T-cell ulative necrosis; the xanthomatous stage manifests lineage origin cause confusion because these cells with foamy histiocytes. are also characteristic of aggressive lymphoma.1,2,4,50 The minimum criteria for a pathological diagno- Necrosis may or may not be present in lymphoma. sis of KFD include the presence of crescent-shaped Immunohistochemical staining, flow cytometry, and histiocytes and plasmacytoid monocytes with molecular clonality studies can help in the differen- scattered karyorrhexis (see Table 2).10,39 It may be tial diagnosis of these 2 disorders. Melikoglu et al55 histiocytic proliferation, not necrosis alone, that is reported lymphadenopathy in 23% to 34% of patients more characteristic of KFD.27 with SLE. The lymph nodes were small, nontender, and generalized in the majority of patients, which is Differential Diagnosis in contrast to patients with KFD. Compared with KFD, A differential diagnosis of KFD is wide and should other clinical and laboratory findings are necessary include infections such as , toxoplasmo- to diagnose SLE.29

A B

C D Fig 1 A-D. — (A) Low power view of a lymph node with involvement by Kikuchi histiocytic necrotizing nonsuppurative lymphadenitis. The pathognomonic pale foci are clues to the collection of histiocytes located in the center between the benign germinal centers located on the left and right sides of the image. (B) Medium power view showing necrosis and pink debris among histiocytes with round- to sickle-shaped nuclei. Well-formed granulomas are not typically seen. (C) Oil magnification showing sheets of pale histiocytic nuclei with violaceous hue and pink cytoplasm showing early findings of the disease with crescentic histiocytes appearing as tingible bodies. This stage is the most often histological appearance mistaken for large cell lymphoma because of the solid appearance of these large cells. Most of these are plasmacytoid monocytes that derive from plasmacytoid dendritic cells. (D) A more advanced stage of Kikuchi–Fujimoto lymphadenitis recognized by pathologists that shows the typical pink necrotizing nodules composed of histiocytic debris. Note the absence of neutrophils or suppurative abscess, which is a hallmark distinguishing this process from the class of suppurative granulomas.

October 2014, Vol. 21, No. 4 Cancer Control 317 Imaging Studies in size, have a shape that is less round, a reticular Imaging studies may be useful in the assessment of echotexture that is less micronodular, and additional patients with peripheral adenopathy. Computed to- signs of matting and cortical widening than those mography helps to differentiate tuberculous lymph- with lymphoma. from KFD. Lee at al56 compared computed to- mographic imaging of the lymph nodes of 24 patients Treatment with KFD and 45 lymph nodes from patients with Treatment guidelines have not been established for tuberculous lymphadenitis. Histologically, differences KFD, and recommendations are based on case reports were seen between KFD and tuberculous lymphade- and expert opinion alone. Due to the self-limited, be- nitis regarding the type of necrosis within the lymph nign course of KFD, observation is the most common nodes. By contrast to tuberculous lymphadenitis, approach in management. Patients with symptoms or which manifests with caseation necrosis surround- with involvement of the extranodal tissues, such as ed with granulomatous tissue, KFD is characteristic the central nervous system, skin, and eyes, can benefit for coagulation necrosis with apoptosis of various from treatment with short pulses of corticosteroids, cell types. These differences may be responsible for nonsteroidal anti-inflammatory drugs, and antipyretics changes seen on imaging studies. Indistinct margins (Fig 2). In patients with complicated KFD, glucocorti- of necrotic foci independently predicted the diagnosis coids or hydroxychloroquine might be useful. Chen et of KFD with 80% accuracy in a multivariate analysis.56 al59 reported a rapid response to hydroxychloroquine Calcifications within the lymph nodes were observed in a child with symptomatic KFD. Yoshioka et al60 in tuberculous lymphadenitis alone compared with treated 13 patients with KFD and prolonged fever with KFD and other lymphoproliferative disorders. a short course of methylprednisolone (0.5 g/day for Tsujikawa et al57 compared the size of lymph 3 days). A dramatic resolution of fever was seen in all nodes and the maximum standardized uptake value patients within 24 hours. Four out of 13 patients (40%) in 8 patients with KFD and 14 patients with non-Hod- relapsed.60 Rezai et al61 treated a patient with KFD who gkin lymphoma using 18F-fluorodeoxyglucose pos- had systemic symptoms with a 4-day course of chlo- itron emission tomography/computed tomography roquine and achieved a rapid response. The patient (FDG PET/CT). The sizes of the lymph nodes were was then re-treated with oral hydroxychloroquine smaller in patients with KFD compared with patients 200 mg twice a day for 14 days for recurrent KFD; with indolent or aggressive . The maximum the patient’s symptoms resolved within 12 hours.61 standardized uptake value was also higher in cases of Yalcin et al62 administered methylprednisolone 1 m/kg KFD compared with indolent non-Hodgkin lymphoma. for 8 days in a symptomatic patient with KFD who A high maximum standardized uptake value in patients achieved a complete resolution of symptoms. The with KFD has been a contributing factor to misdiagno- researchers tapered treatment with steroids by 8 mg sis with aggressive lymphoma (see Table 3).57 every 3 days, leading to the regression of lymphade- Lo et al58 examined ultrasonographic character- nopathy.62 Rezayat et al63 reported on a patient who istics (size, shape, rims, matting, and echotexture) initially responded to therapy with steroids; when in 137 lymph nodes from 21 patients with KFD and the disease recurred, the patient was treated with 89 lymph nodes from 20 patients with malignant lym- single-agent hydroxychloroquine. However, following phoma. Results of this study suggested that cervical the discontinuation of each agent, the disease relapsed in patients with KFD are smaller and the patient required dual therapy.63

Table 3. — Differential Diagnosis of Lymphadenopathy

Variable Kikuchi–Fujimoto Disease Aggressive Lymphoma Systemic Lupus Erythematosus Tuberculosis

Onset Rapid Rapid Slow Slow

Presence of pain Yes No No No

Anatomical distribution Localized Generalized Generalized Localized

Size of lymph nodes 2–4 > 2 2–4 2–5 by CT, cm

FDG/PET avid Yes/High Yes/High Yes/Low, if active disease Yes/Low, if active disease

CT = computed tomography, FDG/PET = 18F-fluorodeoxyglucose positron emission tomography.

318 Cancer Control October 2014, Vol. 21, No. 4 Recurrence Prognosis In a single study, the recurrence rate of KFD was ap- In most patients with KFD, the course of disease is proximately 4%4; however, in a more recent review, benign, with a spontaneous resolution of systemic the recurrence rate was observed to be 15%.41 Bogusz symptoms and adenopathy typically occurring in et al64 identified 65 patients with recurrent KFD in 1 to 4 months.10,27,41 The association of KFD with SLE the published literature until 2013. However, because ranges between 3% and 28% and is higher in Asian approximately 800 cases of KFD have been reported populations.32,41 thus far, the estimated frequency of recurrent KFD In rare instances KFD has a fatal course. The could be less than 10%.32 Recurrences can occur as mortality rate of KFD was reported in 2 large studies long as 8 years after the initial presentation27; there- to be between 0.5% and 2.1%.32,41 The fatal course fore, long-term follow-up is necessary to assess the was due to an infiltration of the myocardium, ce- recurrence rate in KFD. rebral hemorrhage secondary to thrombocytopenia, and an association with SLE and hemophagocytic Pregnancy syndrome.39,41,51,68,69 Few cases have been reported of KFD manifesting during pregnancy. Two reports suggest that treatment Conclusions with antibiotics, steroids, or both have no adverse im- Kikuchi–Fujimoto disease is an idiopathic, rare, benign pacts on the mother, fetus, or throughout the course lymphadenopathy that primarily affects younger peo- of pregnancy.65,66 One miscarriage was described in ple. Since its original description in young Japanese a patient with KFD and evolving SLE.67 females, the disease has been diagnosed in other geo-

Asymptomatic Symptomatic

Nonsteroidal Observation Glucocorticoids Hydroxychloroquine anti-inflammatories

Symptom resolution Persistent symptoms

Observation Workup for simultaneous SLE

Negative Positive

Alternate agent higher doses of Treat SLE glucocorticosteroids and intravenous immunoglobulin

Fig 2. — Therapeutic algorithm. SLE = systemic lupus erythematosus.

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